Table 3.

Mechanisms of anticancer drug resistance

Mechanism	Short description	Ref.
Drug inactivation	Cancer cells generate an alternative mechanism that inactivates the drug that is inside the cell, contributing to modification, degradation, or complex formation. This inactivation decreases the drug’s toxicity levels, and reduces the damage and activity of the drug in cancer cells	[26]
Alteration of drug target	Altered or unrecognized protein structure in the drug’s transporter protein due to accumulated mutations can prevent proper attachment of the drug on its binding site. As a consequence, cancer cells become unable to internalize the cytotoxic drug, leading to their survival	[7,25]
Enhanced efflux pumps	The anticancer drug is pumped out of the cell through a transmembrane protein (efflux pump), preventing the accumulation of the effective drug concentration from causing toxicity in the cell, sabotaging the therapy	[26,29]
DNA-damage repair	Cancer cells may gain the ability to repair the DNA damage/breakage caused by anticancer drugs as a response to promote cell survival	[7,29]
Cell death inhibition	When proteins that induce cell death pathways (apoptosis, necrosis, or autophagy) are mutated or altered, they are unable to induce cell death	[52]
Tumor cell heterogeneity	Cancer cells multiply at an uncontrolled rate, accumulating genetic mutations and epigenetic changes, which lead to resistance and affect their sensitivity to cancer drugs. The generation of cell heterogeneity leads to the development of stem cell-like properties on the new growing cells. The stemness effect is common in cancer cells that are in circulation	[53]
Genetic factors	Include gene mutations, amplifications, and epigenetic alterations. Epigenetic events such as methylation and acetylation affect genetic expression leading to the silencing, overexpression, or amplification of oncogenes or tumor suppressor genes, resulting in the development of cancer drug resistance	[54]